1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Molecular mechanism for Rabex-5 GEF activation by Rabaptin-5

  1. Zhe Zhang
  2. Tianlong Zhang
  3. Shanshan Wang
  4. Zhou Gong
  5. Chun Tang
  6. Jiangye Chen
  7. Jianping Ding  Is a corresponding author
  1. Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China
  2. Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, China
Research Article
  • Cited 19
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Cite this article as: eLife 2014;3:e02687 doi: 10.7554/eLife.02687

Abstract

Rabex-5 and Rabaptin-5 function together to activate Rab5 and further promote early endosomal fusion in endocytosis. The Rabex-5 GEF activity is autoinhibited by the Rabex-5 CC domain (Rabex-5CC) and activated by the Rabaptin-5 C2-1 domain (Rabaptin-5C21) with yet unknown mechanism. We report here the crystal structures of Rabex-5 in complex with the dimeric Rabaptin-5C21 (Rabaptin-5C212) and in complex with Rabaptin-5C212 and Rab5, along with biophysical and biochemical analyses. We show that Rabex-5CC assumes an amphipathic α-helix which binds weakly to the substrate-binding site of the GEF domain, leading to weak autoinhibition of the GEF activity. Binding of Rabaptin-5C21 to Rabex-5 displaces Rabex-5CC to yield a largely exposed substrate-binding site, leading to release of the GEF activity. In the ternary complex the substrate-binding site of Rabex-5 is completely exposed to bind and activate Rab5. Our results reveal the molecular mechanism for the regulation of the Rabex-5 GEF activity.

Article and author information

Author details

  1. Zhe Zhang

    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Tianlong Zhang

    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  3. Shanshan Wang

    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Zhou Gong

    Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Chun Tang

    Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Jiangye Chen

    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Jianping Ding

    Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
    For correspondence
    jpding@sibcb.ac.cn
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Suzanne R Pfeffer, Stanford University, United States

Publication history

  1. Received: March 1, 2014
  2. Accepted: June 20, 2014
  3. Accepted Manuscript published: June 23, 2014 (version 1)
  4. Version of Record published: July 22, 2014 (version 2)

Copyright

© 2014, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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